Small RNA- and DNA-based gene therapy for the treatment of liver cirrhosis, where we are?

Abstract

Chronic liver diseases with different aetiologies rely on the chronic activation of liver injuries which result in a fibrogenesis progression to the end stage of cirrhosis and liver failure. Based on the underlying cellular and molecular mechanisms of a liver fibrosis, there has been proposed several kinds of approaches for the treatment of liver fibrosis. Recently, liver gene therapy has been developed as an alternative way to liver transplantation, which is the only effective therapy for chronic liver diseases. The activation of hepatic stellate cells, a subsequent release of inflammatory cytokines and an accumulation of extracellular matrix during the liver fibrogenesis are the major obstacles to the treatment of liver fibrosis. Several targeted strategies have been developed, such as antisense oligodeoxynucleotides, RNA interference and decoy oligodeoxynucleotides to overcome this barriers. With this report an overview will be provided of targeted strategies for the treatment of liver cirrhosis, and particularly, of the targeted gene therapy using short RNA and DNA segments.

Keywords: Liver cirrhosis, Gene therapy, Oligodeoxynucleotides, Antisense, Small interfering RNA, Micro RNA, Decoy

Core tip: Recent advances in understanding the mechanisms underlying liver fibrogenesis, including regulation of inflammatory cytokine signaling, the dynamic process of hepatic stellate cell activation and extracellular matrix degradation. The only option for patients suffering from severe and late-stage cirrhosis is liver transplantation; however, it is limited by the number of available donor organs. Therefore, development of new therapeutic strategies for liver fibrosis and cirrhosis are needed. This review focuses on the recent advances relating to the therapeutic application of liver fibrogenesis through the modulation of gene expression.